An Extracellular Interactome of Immunoglobulin and LRR Proteins Reveals Receptor-Ligand Networks

Abstract

Extracellular domains of cell-surface receptors and ligands mediate cell-cell communication, adhesion, and initiation of signaling events, but most existing protein-protein “interactome” datasets lack information for extracellular interactions. We probed interactions between receptor extracellular domains, focusing on the Immunoglobulin Superfamily (IgSF), Fibronectin type-III (FnIII) and Leucine-rich repeat (LRR) families of Drosophila, a set of 202 proteins, many of which are known to be important in neuronal and developmental functions. Out of 20503 candidate protein pairs tested, we observed 106 interactions, 83 of which were previously unknown. We ‘deorphanized’ the 20-member subfamily of defective in proboscis IgSF proteins, showing that they selectively interact with an 11-member subfamily of previously uncharacterized IgSF proteins. Both subfamilies interact with a single common ‘orphan’ LRR protein. We also observed new interactions between Hedgehog and EGFR pathway components. Several of these interactions could be visualized in live-dissected embryos, demonstrating that this approach can identify physiologically relevant receptor-ligand pairs.

Incomplete replication generates somatic DNA alterations within Drosophila polytene salivary gland cells

“…As previously noted, one subset of URs corresponds to the major Drosophila Hox gene clusters, and we observed ;10 additional URs containing Polycomb-rich chromatin. Interestingly, we found that URs are also enriched in a class of genes not previously associated with repressive chromatin domains; namely, genes encoding IgG superfamily (IgSF) proteins ( € Ozkan et al 2013). Among the four classes of IgSF proteins characterized by € Ozkan et al (2013), 13 of 14 Beat class, seven of eight Side class, five of 11 DIP class, and nine of 20 Dpr class IgSF genes are in UR regions (Table 1).…”

“…Interestingly, we found that URs are also enriched in a class of genes not previously associated with repressive chromatin domains; namely, genes encoding IgG superfamily (IgSF) proteins ( € Ozkan et al 2013). Among the four classes of IgSF proteins characterized by € Ozkan et al (2013), 13 of 14 Beat class, seven of eight Side class, five of 11 DIP class, and nine of 20 Dpr class IgSF genes are in UR regions (Table 1). Since UR regions constitute only 19% of euchromatin, finding 34 of 53 IgSF genes in UR regions is unlikely to occur by chance (P < 10 À13 ; binomial distribution).…”

“…IgSF genes are expressed on cell surfaces and govern cellular interactions that are important during multiple developmental processes, especially in the nervous system ( € Ozkan et al 2013). Beat proteins are expressed in different subgroups of neural cells (Pipes et al 2001), and some individual family members have been shown to guide motor axons (Fambrough and Goodman 1996).…”

Structural basis for LAR-RPTP/Slitrk complex-mediated synaptic adhesion

“…9c). These structural comparisons indicate that many protein-protein interactions mediated by the extracellular Ig and LRR domain 32 have evolved to serve divergent functions in the CNS through the specific binding of distinct partners.…”

Investigating the role of Dscam2 in the Drosophila mushroom bodies

“…In contrast to the extreme molecular diversity of Dscam1, Drosophila Dscam2 encodes two distinct protein isoforms; Dscam2A and Dscam2B that interact in an isoform-specific homophilic manner (Millard et al, 2007;Ozkan et al, 2013). Cell-specific isoform expression was also previously shown to be important for lamina neuron arborisation (Lah et al, 2014).…”